The effectiveness of fluoride in reducing caries has been well established, and it has been shown that F can affect both the tooth enamel and the acidogenic properties of plaque. Our long-term interest has centered on the inhibitory effect that F exerts on the metabolism of plaque microorganisms. F has been shown to inhibit glycolysis in a large number of streptococci although different strains exhibit different sensitivities toward F. The findings to date do not allow us to fully explain the mechanism of action of F. We have shown that F inhibits streptococcal enolases and, presumably, brings about a reduction in the intracellular concentrations of phosphoenoloyruvate (PEP) and adenosinetriphosphate (ATP). This is believed to be responsible for a reduction of sugar transport into the cells and, ultimately, the dimunition of the rate of acid production. It is reasonable to propose that microorganisms that are relatively resistant to F compensatorily synthesize elevated levels of one or both of the enzyme and carrier systems that participate in sugar transport, or are able to effect changes in the regulatory systems that control glycolysis. Furthermore, we have shown that F can inhibit the proton-translocating ATPase of the cells and may, thereby, have immediate and profound effects on the intracellular pH of the cells. It is possible that the ATPases of different microorganisms respond differently to F. The present research grant application presents a program to examine these proposals and, specifically, outlines experiments that will (a) measure the PEP- and ATP-linked phosphorylating systems that participate in sugar transport, (b) examine the effects that F has on glycolytic intermediates and regulatory processes, and (c) study the inhibition by F of the proton-translocating ATPase comlex in plaque-derived microorganisms. Enzymes will be assayed in decryptified cells with spectrophotometric, NAD-coupled systems. Steady-state levels of glycolytic intermediates will be measured with enzyme-coupled assays or by chromatographic techniques, according to established procedures. It is proposed that such experiments will provide considerable, new insights into the basic mechanisms by which F affects Microbial metabolism and it is likely that these will lead to the development of new approaches for a more effective delivery of the anti-caries agent.